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Chemical augmentations of the Myrmidon Detachment

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40px-Terminal.png This article, Chemical augmentations of the Myrmidon Detachment, was written by RelentlessRecusant. Please do not edit this fiction without the writer's permission.

Introduction to Chemical Biology

Myrmidon augmentation paradigm scheme

The conceptual paradigm for the Myrmidon chemical augmentation initiative, (1) high throughput screening (drug discovery), (2) development of bioactive compounds, and (3) embryonic, physiological, and psychological augmentation.

Myrmidon Small Molecule Pie Chart by Pathway

A pie chart depicting the biological pathways enriched for perturbation by the entire augmentative small molecule collection. Several pathways, such as Wnt (10), MAPK/ERK (4), and Dopamine (4), are notably enriched.

Myrmidon Small Molecule Pie Chart by Organ System

A pie chart depicting the target organ systems of the entire augmentative small molecule collection. Several systems, such as embryonic stem cell (18) and nervous system (16), are notably enriched for perturbation.

"We took twenty years to step back, rethink everything. To change all the augmentations from biological to small-molecule chemical compounds, with augmentations specifically tailored to each child. The entire Myrmidon objectives, core fundamentals, all different. It’s a new world. New SPARTANs for a changing time."
Rear Admiral Kawika Son, 2578[src]


Novel chemical augmentations were one of the foremost goals of the Myrmidon philosophy. Championed by the chemical biologist Beah Schore, the augmentation program of the Myrmidons sought to be the first-ever entirely-chemical augmentation program, with exclusively small-molecule chemical compounds used to augment both the physical and mental attributes of the Myrmidons.

  • Exclusive chemical augmentation: The Myrmidon augmentation program was the first military augmentation program ever to exclusively use small-molecule chemical compounds ("drugs") in the augmentation procedure. While the preceding SPARTAN generations were augmented through a combination of techniques such as high-risk surgeries as well as recombinant proteins, these "biological" effectors were highly discouraged. Surgeries were highly risky, intensive, required special medical talent, and their safety and effects varied substantially from subject to subject, with the benefits and risks varying with the surgeon, the surgical conditions, and the state of the patient. Furthermore, open surgeries were notoriously risky. Other biological augmentations, such as the mutagenic psychoactive proteins employed with the SPARTAN-IIIs of Gamma Company, were similarly disadvantageous because of the in vivo bioavailability of the proteins as well as substantial batch-to-batch variations in the recombinant proteins during manufacturing.
Small molecule augmentations (a "purely chemical" approach) were more advantageous for a number of reasons:
  • Small molecules are widely bioavailable, showing strong distribution and circulation into target tissues[1]
  • Small molecules provide potent control over specific biological targets[2]
  • Small molecules provide rapid temporal control over biological systems[2]
  • Small molecules show dose-controllable control over biological systems[2]
  • Small molecules may provide favorable phenotypes by modulation of a specific target or by modulation of multiple targets[2]
  • Small molecules are technically easy to produce, are cheap, and show no batch-to-batch variation[2]
  • The combinatorial effects of multiple small molecules exerting differential effects over biological systems ("combination chemical genetics") is mathematically simplistic to model and to mathematically understand the effects of drug augmentation[3]
Therefore, the purely chemical augmentation of the Myrmidons provided substantial advantages over "biological" methods of augmentation such as surgeries, recombinant proteins, or viral genetic-delivery vectors.
  • Embryonic augmentation: Previous SPARTAN biological augmentations were restricted in their utility because the augmentations were performed only in adult stages of life. However, Kimberly Ivy Blackburn was a precedent that showed that biochemical modification during embryonic development within the womb could result in augmentations with a dramatically expanded potency; augmentations that modified embryonic development resulted in far more profound changes in physiological and psychological function. However, an exceptional understanding of human developmental biology, based on previous studies of mammalian and invertebrate developmental biology, revealed core signaling pathways that controlled differentiation and tissue specification during development — coupled with chemical biology methods to chemically perturb these select signaling pathways, this allowed for small molecule modification of development to enhance select tissues during development. This allowed for augmentation of the child soldiers even before they were born. Embryonic augumentation had a number of select advantages:
  • Embryonic augmentation allows for extensive augmentation even before birth
  • Because tissues are still plastic and growing during embryogenesis, embryonic augmentation allows for extensive modification of even the basic shape and function of the human body, whereas adult-only augmentation is restricted in its ability to change body physiology and anatomy
  • Embryonic augmentation is painless because of the lack of conscious nociception during development


  • Anatomical Augmentation: While many previous SPARTAN programs and their augmentations sought to control the function ("physiology") of bodily tissues, the Myrmidon Program furthermore sought to modify the actual structure ("anatomy") of the human body and thus control its function. This anatomical modification was primarily achieved through chemical control of embryogenesis; directed self-renewal of pluripotent and multipotent stem cells, combined with directed differentiation, led to vastly increased sizes of various tissues, such as the limb, heart, pancreas, etc...
  • Physiological Augmentation: Furthermore, the Myrmidon Program sought to modify the adult function of tissues. Compounds were employed to increase physical strength, physical endurance, learning, memory, cognition, and other attributes of the nervous system, musculoskeletal system, and other systems. Even de novo properties, such as organ and limb regeneration, were imparted during this phase of adult augmentation.
  • Psychological Augmentation: Both mind and body are integral to warfighting. Therefore, the Myrmidon Program sought to modify the adult mind and psychology as well as anatomy and physiology. Enhanced cognition was a primary target of the Myrmidon Program, with over a dozen compounds imparting increases in learning, memory, attention, reaction time, and executive function. Furthermore, during combat, further psychological modification was performed, with drugs reducing pain and inducing animalistic behavior. The Myrmidon Program believed that combinatorial modification of both bodily physiology and mental psychology would lead to exponential increases in combat potential.


Finally, no less than sixty-two small molecules were chosen to augment the Myrmidon child soldiers throughout all stages of life. These were specific perturbers of human biology at the embryonic, postnatal, and adult stages of life, including both chemical agonists and antagonists to provide quantificable and dose-responsive control over human physiology and psychology with defined desired phenotypic effects and defined off-target side effects. All compounds were real-world compounds originally characterized in the 20th or 21th century.

Bioinformatics and chemical informatics were employed to analyze the composition of the small molecule collection and their annotated biological targets and activities to study the biological perturbers. Through target-pathway clustering, it was found that several key pathways were notably enriched for perturbation (see above).

Notably, eighteen percent of all compounds modulated the Wnt signaling pathway, a key signaling pathway in stem cell biology, differentiation, development, and adult homeostasis and regeneration.[4] The second-most enriched pathways were the dopamine pathway and the MAPK/ERK pathway, both targeted by approximately seven percent of the total collection. The dopamine pathway is a monoamine neurotransmitter pathway that plays key roles in cognition, mood, personality, memory, and stem cell biology.[5][1] The mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK/ERK) pathway is a key mitogenic pathway integral in both stem cell biology and body growth.[6][2][7]

Chemical clustering by target organ system revealed that a full one-third of the collection targeted stem cell systems, mostly embryonic stem cells, demonstrating the actual utility of using small molecules to modulate stem cells for desirable embryonic and adult phenotypes.[2] The second-most enriched target system was the central nervous system and the peripheral nervous system, with nearly thirty percent of the collection modulating nervous activity to generate useful phenotypes such as enhanced cognition and modified psychology and perception.

Manipulation of the human embryo

Chemical augmentation of Myrmidons began at the embryonic stage, with in utero catherization of pregnant women to perfuse developing human embryos with small-molecule compounds to elicit specific effects on human developmental biology.

Phase I: Expansion of pluripotent stem cells

HES capture of authentic pluripotency

Capture of authentic ground state pluripotency from the human inner cell mass (ICM). Ten chemical compounds promote embryonic stem cell self-renewal and block apoptosis and differentiation (see below) to expand the human pluripotent progenitor cell pool.

Firstly, compounds were employed to inhibit the maturation of the human pluripotent inner cell mass (ICM) to the epiblast, maintaining the "ground state" pluripotency of authentic pluripotent cells in the human inner cell mass.[8] This blockade of embryonic maturation allowed for the continual self-renewal and expansion of human embryonic stem (hES) cells, enlarging the pluripotent progenitor pool and allowing for increased numbers of differentiated cells to be formed in embryonic and adult life, increasing mean body size and organ mass.

In order to employ chemical probes to blockade pluripotent stem cell differentiation and maturation, Beah Schore composed a collection of compounds known to either enhance embryonic stem cell self-renewal or to specifically block the differentiation of embryonic stem cells to certain lineages.

Finally, ten small-molecule compounds were chosen for final employment.

An Activin receptor and Nodal receptor inhibitor, A-83-01 ("A8"), was employed to block stem cell differentiation to the definitive endoderm.[9][10] A bone morphogenetic protein receptor (BMPR) inhibitor, Dorsomorphin ("DM"), was employed to block stem cell differentiation to the mesodermal lineage.[11] A fibroblast growth factor receptor (FGFR) inhibitor, SU5402 ("S5") and an extracellular signal-regulated kinase (ERK) inhibitor, PD184352 ("P1"), were employed to block stem cell differentiation to both the neuroectodermal and mesodermal lineages.[12][6] Cells that managed to escape the chemical blockade and begin differentiation were rapidly de-differentiated by a mitogen-activated protein kinase (MAPK) and a nonmuscle myosin II heavy chain inhibitor, Reversine ("RV").

Overexpression of Nanog, a key member of the pluripotent transcriptome, has been shown to render stem cells refractory to differentiation, whereas deficiency of Nanog (Nanog-/-) has been shown to render pluripotent cells towards differentiation to multiple lineages, including the primitive endoderm. Because β-catenin and canonical Wnt signaling has been shown to increase Nanog expression, a glycogen synthase kinase 3 (GSK3) inhibitor, CHIR99021 ("C9"), was employed to inhibit the global differentiation of pluripotent stem cells.[13]

A p160-Rho-associated coiled-coil kinase (ROCK) inhibitor, Y-27632 ("Y2"), was employed to inhibit the apoptosis of pluripotent stem cells and to enhance their survival.[14]

Finally, three final compounds were chosen to specifically induce the self-renewal of stem cells. These included a Ras GTPase-activating protein (RasGAP) and an extracellular signal-regulated kinase (ERK) inhibitor, Pluripotin ("SC")[15], and two natural products with uncharacterized biological targets, Theanine ("TN") and Flurbiprofen ("FP").

Thus, in conclusion, combinatorially, these ten compounds potently blocked the maturation of the inner cell mass (ICM) and the loss of pluripotency by blockade of differentiation, enhancement of stem cell survival, and enhancement of stem cell self-renewal.


Chemical expansion of the pluripotent inner cell mass
Chemical Name Abbreviation Phenotypic Effect Biological Target Mechanism
A-83-01 "A8" Inhibition of differentiation TGFβ/Activin Receptors Repression of endodermal differentiation
Dorsomorphin "DM" Inhibition of differentiation TGFβ/BMP Receptors Repression of mesodermal differentation
SU5402 "S5" Inhibition of differentiation FGFR1 Repression of endodermal and mesodermal differentiation
PD184352 "P1" Inhibition of differentiation MAPK/ERK Repression of endodermal and mesodermal differentiation
CHIR99021 "C9" Inhibition of differentiation GSK3 Activation of Wnt signaling and Nanog expression
Reversine "RV" Reversal of differentiation Polypharmacological De-differentiation of differentiated cells
Y-27632 "Y7" Inhibition of apoptosis ROCK Suppression of chemically-induced apoptosis
Pluripotin "SC" Promotion of self-renewal RasGAP and MAPK/ERK Long-term renewal of embryonic stem cells
Theanine "TN" Promotion of self-renewal Unknown Short-term renewal of embryonic stem cells
Flurbiprofen "FP" Promotion of self-renewal COX-2 Short-term renewal of embryonic stem cells


Inhibitors of stem cell differentiation
A-83-01

The chemical structure of A-83-01, a TGFβ/Activin receptor inhibitor.

  • A-83-01: Chemical inhibitor of TGFβ/Activin receptors, specifically the activin receptor (ALK4), the TGF-β receptor (ALK5), and the nodal receptor (ALK7)[9][16]
Chemical Name: 3-(6-Methylpyridin-2-yl)-1-phenylthiocarbamoyl-4-quinolin-4-ylpyrazole[17][9]
Biological Target: ACVR1B (ALK4), TGFβRI (ALK5), ACVR1C (ALK7)[9]
Biological Activity: Blockade of embryonic stem (ES) cell differentiation to the definitive endoderm, maintaining the pluripotency of human pluripotent stem cells and expanding the pluripotent progenitor pool
Biological Annotation: Activin and Nodal signals of the TGFβ family are responsible for the differentiation of pluripotent stem cells to the definitive endoderm. Suppression of TGFβ signals leads to blockade of endodermal differentiation.[18][19][10][20]


Dorsomorphin

The chemical structure of Dorsomorphin, a TGFβ/BMP receptor inhibitor.

  • Dorsomorphin: Chemical inhibitor of TGFβ/BMP receptors, specifically ActRIA (ALK2), BMPRIA (ALK3), and BMPR1B (ALK6)[11]
Chemical Name: 6-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine[11]
Biological Target: ActRIA (ALK2), BMPRIA (ALK3), and BMPR1B (ALK6)[11]
Biological Activity: Blockade of embryonic stem (ES) differentiation to the mesoderm, maintaining the pluripotency of human pluripotent stem cells and expanding the pluripotent progenitor pool
Biological Annotation: Dorsomorphin is a specific inhibitor of ALK2, ALK3, and ALK6, serving to block transmission of BMP signals, specifically BMP-2, BMP-4, BMP6, and BMP-7 and subsequent phosphorylation of SMADs. The requirement of BMP signals in gastrulation for mesodermal specification means that suppression of BMP signaling in the pluripotent inner cell mass leads to repression of the mesodermal lineage.[11]


SU5402

The chemical structure of SU5402, an FGFR1 inhibitor.

  • SU5402: Chemical inhibitor of fibroblast growth factor receptor 1 (FGFR1)[21]
Chemical Name: 3-[(3-(2-carboxyethyl)-4-methylpyrrol-2-yl)methylene]-2-indolinone[21]
Biological Target: FGFR1 (Fibroblast Growth Factor Receptor 1)
Biological Activity: Blockade of embryonic stem cell (ES) differentiation to the endoderm and mesoderm, maintaining the pluripotency of human pluripotent stem cells and expanding the pluripotent progenitor pool[6]
Biological Annotation: Fgfr1 and Fgf4 are extensively implicated in stem cell biology and developmental biology. FGF4, an FGFR1 ligand[22], activates the ERK pathway in embryonic stem cells and inhibits their self-renewal, instead inducing differentiation to the mesodermal and endodermal lineages.[12] Blockade of FGFR1 by SU5402 leads to repression of differentiation-inducing FGF signaling and reduces the competence of embryonic stem cells to differentiate, instead promoting self-renewal.[12][6]
Structural Mechanism: Competitively binds to the ATP-binding site on FGFR1 protein, inhibiting kinase activity by competing with ATP. Interacts with FGFR1 trough three separate intermolecular interactions with the kinase domain in a hydrophobic haven, and demonstrates even electron distribution.[21]


PD184352 structure

The chemical structure of PD184352, a MAPK/ERK inhibitor.

  • PD184352: Chemical inhibitor of the MAPK/ERK pathway[6]
Chemical Name: 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
Biological Target: Mitogen-activated protein kinase kinase (MKK1)[23]
Biological Activity: Blockade of embryonic stem cell (ES) differentiation to the endoderm and mesoderm, maintaining the pluripotency of human pluripotent stem cells and expanding the pluripotent progenitor pool[6]
Biological Annotation: ERK is phosphorylated upon FGF4 signaling, triggering lineage commitment of embryonic stem cells, and phospho-ERK is indeed required for endodermal or mesodermal differentiation of embryonic stem cells.[12] Inhibition of the MAPK/ERK pathway with PD184352 leads to repression of the autoinductive FGF4 signal, encouraging pluripotency and embryonic stem cell self-renewal.[6]


CHIR99021

The chemical structure of CHIR99021, a GSK3 inhibitor.

  • CHIR99021: Chemical inhibitor of GSK3β, activator of canonical Wnt signaling and Nanog expression
Chemical Name: 6-(2-(4-(2,4-dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)pyrimidin-2-ylamino)ethylamino)nicotinonitrile
Biological Target: Glycogen synthase kinase 3 (GSK3α/β), IC50 = 6.7 nM[24]
Biological Activity: Globally blocks pluripotent stem cell differentiation to all lineages, leading to the maintenance of pluripotency of human pluripotent stem cells and expanding the pluripotent progenitor pool[6]
Biological Annotation: GSK3β is a biological inhibitor of Wnt signaling, and Wnt signaling is implicated in stem cell self-renewal, controlling the embryonic stem cell transcriptome and cell cycle.[25] The role of Wnt signaling in stem cell self-renewal is believed to be through activation of Nanog transcription[26], and Nanog is a core member of the pluripotency transcriptome, actively suppressing differentiation and safeguarding against loss of pluripotency.[27] GSK3 inhibition and Wnt signaling has been shown to blockade stem cell differentiation and lead to embryonic stem cell self-renewal.[6]


Reversine structure

The chemical structure of reversine, a promiscuous chemical inhibitor.

  • Reversine: Polypharmacological inhibitor of multiple kinases and receptors
Chemical Name: 2-(4-morpholinoanilino)-N6-cyclohexyladenine
Biological Target: Aurora kinase A, Aurora kinase B, Adenosine receptor A3, MEK1, and Myosin II Heavy Chain[28][29]
Biological Activity: De-differentiates differentiating cells, leading to reprogramming of differentiated cells to authentic pluripotent stem cells and maintenance of the pluripotent progenitor pool through indirect inhibition of differentiation
Biological Annotation: Reversine has been shown to de-differentiate myoblasts to a putative multipotent mesenchymal stem cell (MSC)-like intermediate, relaxing lineage specificity and leading to ectopic expression of mesodermal and neuroectodermal transcripts.[28][29]


Inhibitors of stem cell apoptosis
Y27632 structure

The chemical structure of Y-27632, a ROCK inhibitor.

  • Y-27632: Chemical inhibitor of p160-Rho-associated coiled-coil kinase (ROCK)[30]
Chemical Name: (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide
Biological Target: p160-Rho-associated coiled-coil kinase (ROCK)[30]
Biological Activity: Blocks apoptosis of cells of the pluripotent inner cell mass, leading to increased numbers of pluripotent progenitors[14]
Biological Annotation: ROCK family kinases are responsible for cell cycle regulation and control of apoptosis.[31] Blockade of ROCK signaling through Y-27632 has been shown to improve the survival of dissociated human embryonic stem cells, putatively through the inhibition of chemically-induced apoptosis.[14] Y-27632 is believed to play a similar role in enhancement of the survival of pluripotent human inner cell mass.


Enhancers of stem cell self-renewal
Pluripotin structure

The chemical structure of pluripotin, a dual RasGAP and ERK inhibitor.

  • Pluripotin: Polypharmacological inhibitor of both RasGAP and ERK1/2[15]
Chemical Name: N-(3-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide[15]
Biological Target: Ras GTPase-activating protein (RasGAP) and extracellular signal-regulated kinase (ERK)
Biological Activity: Sustains self-renewal of embryonic stem cells, leading to increased numbers of pluripotent progenitors
Biological Annotation: Murine embryonic stem cells spontaneously differentiate, and require both leukemia inhibitory factor (LIF) and murine embryonic fibroblast (MEF) feeder layers to sustain self-renewal. Pluripotin replaces the dual requirement for LIF and feeders, and stem cells cultured in the presence of pluripotin maintain their pluripotency and can be expanded indefinitely in culture in chemically-defined conditions. [2][15]


Theanine structure

The chemical structure of theanine, a natural product.

  • Theanine: Natural product derived from Camellia sinensis and Boletus badius
Chemical Name: 2-amino-4-(ethylcarbamoyl)butyric acid
Biological Target: Uncharacterized
Biological Activity: Sustains self-renewal of the human pluripotent inner cell mass, leading to increased numbers of pluripotent progenitors
Biological Annotation: Theanine was identified through a high-throughput screen to maintain short-term pluripotency of human embryonic stem (hES) cells in the absence of FGF2.[32] As theanine has been shown to increase central nervous system (CNS) concentrations of γ-aminobutryic acid (GABA), its role in embryonic stem cell proliferation is contradictory, as it has been shown that autocrine or paracrine GABAergic signnaling in stem cell cultures leads to repression of embryonic stem cell proliferation.[33]


Flurbiprofen structure

The chemical structure of flurbiprofen, a selective COX-2 inhibitor.

  • Flurbiprofen: Chemical inhibitor of cyclooxygenase 2 (COX-2)
Chemical Name: 2-(3-fluoro-4-phenyl-phenyl)propanoic acid
Biological Target: Cyclooxygenase 2 (COX-2)
Biological Activity: Sustains self-renewal of the human pluripotent inner cell mass, leading to increased numbers of pluripotent progenitors
Biological Annotation: Flurbiprofen was identified through a high-throughput screen to maintain short-term pluripotency of human embryonic stem (hES) cells in the absence of FGF2.[32] Although its precise molecular mechanism is unknown, fluribprofen's activity as an anti-inflammatory agent is mediated through inhibition of protein and leukocyte migration, inhibition of prostaglandin synthesis, stabilization of the cell membrane, and activation of mitochondrial ATPase.[34]


Phase II: Chemically-directed differentiation to germ layers

During the first days of embryogenesis, embryonic development was arrested by the ten chemical compounds employed in "Phase I" of the augmentation, producing a vastly-expanded pool of pluripotent progenitors in the human inner cell mass (ICM), increasing the number of embryonic stem cells ready to undergo development, expanding the number of differentiated cells to be possibly developed in development. However, specification of the three primary germ layers (definitive endoderm, mesoderm, and neuroectoderm) was necessary.

Therefore, in the succeeding days, seven small molecules were employed to efficiently differentiate the expanded pluripotent progenitor pool, transitioning them sequentially from the inner cell mass to the patterning epiblast and the primitive streak (mesendoderm), and later, to the three major germ lineages.

Because during the first phase, pluripotent stem cells were potently stimulated to proliferate and self-renew, it was necessary to de-orbit them from their pluripotency program and instead to transition them to a state amenable to differentiation. This was achieved by employing stauprimide ("SP"), an indirect inhibitor of c-myc, therefore decreasing stem cell proliferation and making them receptive to differentiation cues.[35]

Next, either the mesendoderm or the neuroectoderm was established by a simple fate switch; the presence or absence of TGFβ signaling.

Two putative histone deacetylase (HDAC) inhibitors, IDE1 ("I1") and IDE2 ("I2")[36], were used to indirectly mimic TGFβ/Activin signaling, specifying a mesendodermal fate in a subset of cells, along with the GSK3 inhibitor BIO-Acetoxime ("BA") to stimulate the Wnt pathway, formatively creating the mesendoderm.[37] Cymarin ("CY"), a cardiac glycoside known to induce SOX17 expression in embryonic stem cells, was used ancillarily to specify the definitive endoderm.[32]

The TGFβ/Activin receptor inhibitor SB431542 ("S1") was employed to inhibit Activin signaling in a subset of cells, diverting them from endodermal differentiation and instead specifying the neuroectoderm in the absence of defining signals.[38] This was further confirmed by selegiline ("SE"), a selective MAOA inhibitor previously shown to encourage the development of the neuroectoderm.[32]



Chemical specification of germ lineages
Chemical Name Abbreviation Phenotypic Effect Biological Target Mechanism
Stauprimide "SP" Priming of stem cells for differentiation NME2 Repression of stem cell proliferation
BIO-Acetoxime "BA" Differentiation to mesendoderm GSK3 Activation of Wnt signaling
Cymarin "CY" Differentiation to definitive endoderm Na+/K+ pump Molecular mechanisms unknown
IDE1 "I1" Differentiation to definitive endoderm Unknown Activation of SMAD2 phosphorylation
IDE2 "I2" Differentiation to definitive endoderm Unknown Activation of SMAD2 phosphorylation
Selegiline "SG" Differentiation to neuroectoderm MAOA Molecular mechanisms unknown
SB431542 "S4" Differentiation to neuroectoderm TGFβ/Activin receptors Blockade of endodermal TGFβ signaling


Dysregulation of pluripotent stem cell self-renewal
Stauprimide structure

The chemical structure of stauprimide, an NME2 inhibitor.

  • Stauprimide: Chemical inhibitor of NME2 and downregulator of c-myc[35]
Biological Target: NME2 (Nonmetastatic cells, protein expressed in-2)[35]
Biological Activity: Primes pluripotent stem cells for differentiation, enhancing differentiation of the pluripotent inner cell mass to all lineages and increasing the number of differentiated cells produced
Biological Annotation: C-myc is a core component of the pluripotency transcriptome, regulating cell proliferation and chromosomal accessibility through chromatin remodeling.[39] Stauprimide was characterized as an NME2 inhibitor, thereby downregulating c-myc expression, thus, stauprimide was found to globally enhance the differentiation efficiency of human (hES) and murine (mES) embryonic stem cells to all lineages, including endodermal, mesodermal, and neuroectodermal, suggesting that it exits pluripotent stem cells from pluripotency and self-renewal and forces them into an activated state that is receptive and sensitized for pan-lineage differentiation.[35]


Chemical differentiation to the mesendoderm
BIO-Acetoxime Structure

The chemical structure of BIO-Acetoxime, a GSK3 inhibitor.

  • BIO-Acetoxime: Chemical inhibitor of glycogen synthase kinase 3 (GSK3)[40]
Chemical Name: (2′Z,3′E)-6-Bromoindirubin-3′-acetoxime
Biological Target: Glycogen synthase kinase 3 (GSK3)
Biological Activity: Differentiates the embryo to the mesendoderm (primitive streak), defining formation of the definitive endoderm and the mesoderm[37]
Biological Annotation: BIO-acetoxime is a GSK3 inhibitor, and therefore is an activator of Wnt signaling.[25] Wnt signaling in the developing embryo sequentially specifies the mesendoderm and later, the mesoderm.[37]


Cymarin structure

The chemical structure of cymarin, an inhibitor of the Na+/K+ pump.

  • Cymarin: Chemical inhibitor of the Na+/K+ pump
Chemical Name: (3S,5S,8R,10S,13R,14S,17R)-5,14-dihydroxy-3-((2R,4S,5S,6R)-5-hydroxy-4-methoxy-6-methyltetrahydro-2H-pyran-2-yloxy)-13-methyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-10-carbaldehyde
Biological Target: Na+/K+ pump
Biological Activity: Differentiates the embryo to the definitive endoderm[32]
Biological Annotation: Molecular mechanism of action unknown


IDE1 structure

The chemical structure of IDE1, a putative histone deacetylase inhibitor.

  • IDE1: Putative chemical inhibitor of histone deacetylases (HDAC)[36]
Chemical Name: 2-[(6-carboxyl-hexanoyl)-hydrazonomethyl]-benzoic acid[36]
Biological Target: Chemically-biased to inhibit histone deacetylases (HDAC)[36]
Biological Activity: Differentiates the embryo to the definitive endoderm[36]
Biological Annotation: Differentiates human embryonic stem (hES) and murine embryonic stem (mES) cells to the definitive endoderm with comparable efficiency as Activin A, and indirectly activates TGFβ/Activin signaling.[36]


IDE2 structure

The chemical structure of IDE2, a putative histone deacetylase inhibitor.

  • IDE2: Putative chemical inhibitor of histone deacetylases (HDAC)[36]
Chemical Name: 7-(2-cyclopentylidenehydrazino)-7-oxohepatanoic acid[36]
Biological Target: Chemically-biased to inhibit histone deacetylases (HDAC)[36]
Biological Activity: Differentiates the embryo to the definitive endoderm[36]
Biological Annotation: Differentiates human embryonic stem (hES) and murine embryonic stem (mES) cells to the definitive endoderm with comparable efficiency as Activin A, and indirectly activates TGFβ/Activin signaling.[36]


Chemical differentiation to the neuroectoderm
Selegiline

The chemical structure of selegiline, a monoamine oxidase B (MAOB) inhibitor.

Chemical Name: (R)-N-methyl-N-(1-phenylpropan-2-yl)prop-2-yn-1-amine
Biological Target: Monoamine oxidase B (MAOB)
Biological Activity: Differentiates the embryo to the neuroectoderm[32]
Biological Annotation: Molecular mechanisms unknown


SB431542 structure

The chemical structure of SB431542, a TGFβ/Activin receptor inhibitor.

  • SB431542: Chemical inhibitor of TGFβ/Activin receptors, specifically the activin receptor (ALK4), the TGF-β receptor (ALK5), and the nodal receptor (ALK7)[42]
Chemical Name: 4-(5-Benzol[1,3]dioxol-5-yl-4-pyrldin-2-yl-1H-imidazol-2-yl)-benzamide
Biological Target: ACVR1B (ALK4), TGFβRI (ALK5), ACVR1C (ALK7)[42]
Biological Activity: Differentates the embryo to the neuroectoderm[42]
Biological Annotation: In development, a variety of signals of the TGFβ/Activin, TGFβ/BMP, FGF, and Wnt familes act during gastrulation to specify the mesoderm and endoderm.[38] However, an absence of these signals leads instead to the specification of the neuroectoderm — indeed, the neuroectodermal domain is expanded by ectopic blockade of BMP or TGFβ.[38] Suppression of TGFβ/Activin signaling by SB431542 represses endodermal differentiation cues and aides in differentiation to the neuroectoderm.


Phase III: Chemically-directed multipotent stem cell specification

During the prior phases of the embryonic Myrmidon augmentation, the pluripotent inner cell was first expanded, then directed to differentiate into the three major germ lineages. Subsequently, during "Phase III" of the augmentation, multipotent stem cells would be specified from these germ lineages, leading to substantially enhanced numbers of the differentiated cells generated from those multipotent stem cells.

From the definitive endoderm, multipotent pancreatic progenitors[43] were specified by activation of protein kinase C (PKC) signaling. Treatment with a PKC agonist, (—)-Indolactam V ("IV"), would substantially increase the number of pancreatic progenitors specified.[44][45]

From the mesoderm, both cardiovascular stem cells and haematopoietic stem cells would be specifically induced, contributing to increased heart mass and increased haematopoietic cells, respectively.

Cardiovascular progenitors in development are both pre-specified and self-renewed by Wnt/β-catenin signaling[46], therefore the GSK3 inhibitor SB-216763 ("S2") was employed to activate Wnt signaling and to substantially increase the number of multipotent cardiovascular stem cells generated.[46][47]

Haematopoietic stem cells are embryonically specified and renewed by the combined cyclooxgenase (COX)—prostaglandin pathway, and therefore, a leukotriene D4 receptor antagonist, LY 171883 ("L1")[48], was employed to significantly increase the number of developmental haematopoietic stem cells.[49]


Chemical specification and renewal of multipotent stem cells
Chemical Name Abbreviation Phenotypic Effect Biological Target Mechanism
SB-216763 "S2" Substantially increased heart size GSK3 Increased specification and renewal of cardiovascular progenitors
LY 171883 "L1" Increased haematopoietic cell number LD4 receptor Increased specification and renewal of haematopoietic stem cells
(—)-Indolactam V "IV" Increased pancreas size PKC Increased specification or renewal of pancreatic progenitors


Cardiovascular stem cell specification
SB 216763 structure

The chemical structure of SB-216763, a GSK3 inhibitor.

  • SB-216763: Chemical inhibitor of glycogen synthase kinase (GSK3)[47]
Chemical Name: 3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyr role-2,5-dione[47]
Biological Target: Glycogen synthase 3 (GSK3), IC50 = 34.3 nM[47]
Biological Activity: Leads to greatly increased numbers of embryonic cardiovascular progenitors (MICPs), leading to highly increased numbers of cardiac muscle, smooth muscle, and endothelial vasculature[46]
Biological Annotation: Specification and self-renewal of cardiovascular progenitors are controlled by the Wnt/β-catenin signaling pathway[46], and inhibition of GSK3 by SB-216763 leads to Wnt pathway activation and subsequent increase in pre-specification and self-renewal of human cardiovascular progenitors.[25][46]


Haematopoietic stem cell specification
LY 171883 Structure

The chemical structure of LY 171883, a leukotriene D4 receptor antagonist.

  • LY 171883: Chemical inhibitor of the leukotriene D4 receptor[48]
Chemical Name: 1-[2-Hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl]ethanone[48]
Biological Target: Leukotriene D4 receptor[48]
Biological Activity: Leads to greatly increased numbers of haematopoietic stem cells during development[49]
Biological Annotation: The linked cyclooxygenase (COX) and prostaglandin pathways have been shown to be both necessary and integral in the developmental specification and self-renewal of embryonic haematopoietic stem cells.[49] Modulation of prostaglandin signaling by LY 171883 leads to a marked increase in the number of haematopoietic stem cells.[49]


Pancreatic progenitor specification
ILV

The chemical structure of (—)-Indolactam V, a protein kinase C (PKC) agonist.

  • (—)-Indolactam V: Chemical agonist of protein kinase C (PKC)[44][45]
Biological Target: Protein kinase C (PKC)[44][45]
Biological Activity: Substantially increases the number of multipotent pancreatic progenitors and the number of downstream endocrine β-cells produced[44][43]
Biological Annotation: PKC signaling appears to necessary for either the induction or expansion of pancreatic progenitors, and PKC inhibitors severely depress the numbers of pancreatic progenitors.[44] Conversely, PKC activation by (—)-Indolactam V causes a substantial increase in the number of human pancreatic progenitors.[44] (—)-Indolactam V directly specifies the multipotent embryonic pancreatic domain from the definitive endoderm at the expense of hepatic specification, and does not increase the efficiency of initial allocation to the definitive endoderm.[44]


Phase IV: Chemically-directed terminal differentiation


Chemical specification of differentiated embryonic tissues
Chemical Name Abbreviation Phenotypic Effect Biological Target Mechanism
Tianeptine "TN" Increased vision and tactile perception SERT Enhanced maturation of visual and somatosensory cortices
L-AP4 "LA" Increased brain mass and neuronal mass mGluR4 Increased differentiation to neurons
All-trans retinoic acid "RA" Increased pancreas size and β-cell mass RAR Increased pancreatic and β-cell specification
Trichostatin A "TA" Increased pancreas size and β-cell mass HDAC Increased pancreatic and β-cell specification
PK115-584 "P1" Increased lung size Tcf4/β-catenin Distal lung expansion
Compound E "CE" Increased lung size γ-secretase Enhancement of aveolar differentiation
LDN-193189 "L1" Increased arm and leg size TGFβ/BMP receptors Augmentation of FGF-SHH signaling


Differentiation to neurons
Tianeptine structure

The chemical structure of tianeptine, a serotonin transporter activator.

  • Tianeptine: Chemical activator of the serotonin transporter[50]
Chemical Name: 7-(3-Chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide
Biological Target: Serotonin transporter (SERT)[50]
Biological Activity: Enhances visual and tactile sensation
Biological Annotation: Genetic deletion of MAOA leads to substantially elevated serotonin levels and disorganization of the visual and somatosensory cortices, leading to severe visual and somatosensory impairment.[51] Tianeptine has the reverse effect, reducing serotonin levels by activating the serotonin transporter, leading to enhanced development of the visual and somatosensory cortices and enhanced sensation.


L-AP4 Structure

The chemical structure of L-AP4, an agonist of group III metabolic glutamate receptors.

  • L-AP4: Chemical agonist of group III metabotropic glutamate receptors (mGluR)[52]
Chemical Name: L-(+)-2-Amino-4-phosphonobutyric acid
Biological Target: Group III metabotropic glutamate receptors (mGluRs)[52]
Biological Activity: Increases the neurons developed during development
Biological Annotation: Activation of group III metabotropic glutamate receptors potently differentiates neural stem cells to neurons, and improves neuronal survival.[52] Specifically, this effect appears to be mediated through mGluR4 — mGluR4 activity inhibits the proliferation of neurospheres and induces neurogenic commitment.[52]


Differentiation to the pancreas
All-trans retinoic acid structure

The structure of all-trans retinoic acid, an endogenous ligand for retinoic acid receptors (RARs).

  • All-trans retinoic acid: Chemical activator and endogenous ligand for the retinoic acid receptors (RARs)[53]
Chemical Name: (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid
Biological Target: RARα ("Retinoic acid receptor alpha"), RARβ ("Retinoic acid receptor beta"), and RARγ ("Retinoic acid receptor gamma")[53]
Biological Activity: Creates an enlarged pancreas with especially high numbers of endocrine β-cells
Biological Annotation: Retinoid signaling plays an integral role in pancreatic development.[54][55][56] Retinoid signaling is integral for development of the dorsal endoderm and for the formation of the pancreas[55], and it has been shown that not only does retinoic acid signaling specify the pancreas, but that retinoic acid expands pancreatic endocrine progenitors[56] and greatly increases the number of differentiated pancreatic endocrine cell types formed[56][55], also acting to directly specify insulin-secreting β-cells.[54]


Trichostatin A Structure

The chemical structure of trichostatin A, a histone deacetylase inhibitor.

  • Trichostatin A: Chemical inhibitor of Class I and Class II histone deacetylases (HDACs)[57]
Chemical Name: R-(E,E)]-7-[4-(Dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxo-2,4-heptadienamide
Biological Target: Class I and Class II histone deacetylases (HDACs)
Biological Activity: Creates especially high numbers of pancreatic endocrine cells, especially insulin-secreting β-cells[57]
Biological Annotation: Histone deacetylases are downregulated during pancreatic development, suggesting that their repression is permissive to pancreatic differentiation.[57] Histone deacetylase inhibition leads to promotion of pro-endocrine progenitors at the expense of endocrine differentiation, and trichostatin A has been shown to especially enhance the formation of insulin-secreting β-cells and somatostatin-secreting δ-cells.[57]


Differentiation to the lungs
Calphostin C

The chemical structure of PK115-584, a Tcf4/β-catenin inhibitor.

  • PK115-584: Chemical inhibitor of the Tcf4/β-catenin interaction[58]
Chemical Name: 1-[3,10-dihydroxy-12-[2-(4-hydroxyphenoxy)carbonyloxypropyl]-2,6,7, 11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl benzoate
Biological Target: Tcf4/β-catenin, protein kinase C (PKC), and myosin light chain kinase (MLCK)[58]
Biological Activity: Increased lung size[59]
Biological Annotation: Wnt5a-/- mice demonstrate increased embryonic lung epithelium and mesenchyme proliferation, resulting in expansion of the distal lung and increased lung size.[59] This phenotype was mimicked by PK115-584, which is a promiscuous inhibitor of the Wnt signaling pathway that acts by inhibiting the Tcf4/β-catenin interaction.[58]


Compound E

The chemical structure of Compound E, a γ-secretase inhibitor.

Chemical Name: (S)-2-(2-(3,5-difluorophenyl)acetamido)-N-((S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanamide
Biological Target: Presenilin-1 (PS1)[60]
Biological Activity: Increased aveolar size and volume
Biological Annotation: Notch signaling is influential in lung development, arresting distal lung progenitors before they can commit to an aveolar differentiation program, serving to inhibit aveolar development and differentiation.[61] Conversely, Notch inhibition by Compound E acted instead to increase commitment to aveolar differentiation, increasing aveolar size and volume.


Differentiation to the limb mesenchyme
Dorsomorphin Analog

The chemical structure of LDN-193189, an inhibitor of TGFβ/BMP receptors.

  • LDN-193189: Chemical inhibitor of TGFβ/BMP receptors, specifically ActRIA (ALK2), BMPRIA (ALK3), and BMPR1B (ALK6)[62]
Chemical Name: 4-(6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline
Biological Target: ActRIA (ALK2), BMPRIA (ALK3), and BMPR1B (ALK6)[62]
Biological Activity: Increases the size of leg and arms
Biological Annotation: During embryogenesis, limb specification and growth is controlled by a highly complex auto-regulatory loop comprised of the genes Grem1, Fgf4, Fgf8, and Shh.[63] Gremlin (Cktsf1b1, Grem1) is an endogenous BMP antagonist that is necessary for proper limb development.[64] Unopposed BMP signaling leads to repression of expression of FGF signals, and blockade of BMP transmission specifically by Gremlin is required for proper induction of Fgf4 and Fgf8 and proper subsequent limb formation by a Fgf-Shh cascade.[64] In the developing mesenchyme, BMP is potently co-repressed by LDN-193189, a synthetic inhibitor of BMP receptors[62], leading to an expanded domain of BMP-negative cells and expansion of the developing limbs, leading to enlarged legs and arms.

Augmentation of the adult human


Chemical augumentation of the adult human
Chemical Name Abbreviation Phenotypic Effect Biological Target Mechanism
A-769662 "A7" ↑ Physical endurance and strength AMPK Metabolism enhancement and muscle fiber reprogramming
GW501516 "G5" ↑ Physical endurance and strength PPARδ Mitochondrial modification and muscle fiber reprogramming
Resveratrol "RT" ↑ Lifespan and ↑ Physical endurance and strength AMPK & Sirtuin 1 Metabolism enhancement and muscle fiber reprogramming
SRT1720 "S1" ↑ Physical endurance and strength Sirtuin 1 Metabolism enhancement and muscle fiber reprogramming
NP549 "N5" Increases muscle mass GSK3 Muscle recruitment of hematopoietic stem cells
T0070907 "T0" Converts brown fat to muscle PPARγ Reprogramming of brown adipocytes to skeletal myocytes
FPL 64176 "F6" ↑ Learning and memory L-type Ca+2 channels Enhanced long-term potentiation (LTP), synaptic plasticity
(S)-(-)-Sulpiride "SP" ↑ Memory storage capacity, ↑ Learning & memory D2/D3 receptors Increased adult neurogenesis
Compound 9 "C9" ↑ Memory storage capacity, ↑ Learning & memory NMDA receptor Increased adult neurogenesis
QS11 "Q1" ↑ Memory storage capacity, ↑ Learning & memory ARFGAP1 Increased adult neurogenesis
Neuropathiazol "NP" ↑ Memory formation Unknown Increased adult hippocampal neurogenesis
TWS119 "T1" ↑ Memory storage capacity, ↑ Learning & memory GSK3β Increased adult neurogenesis
(S)-(-)-Cotinine "CT" ↑ Memory and ↑ Attention α3β2/α6β2 nAChRs Increased cholinergic forebrain transmission
O-1783 "O1" ↑ Decision making, ↑ Reaction time, ↑ Attention Dopamine transporter Increased dopaminergic transmission
Hh-Ag1.5 "H5" Forms new large blood vessels Smoothened Induction of angiogenic signals
SNAP "SA" ↑ Blood flow and forms new blood vessels Nitric oxide donor Vasodilation and hematopoietic stem cell mobilization
Prostaglandin E2 "E2" ↑ Red blood cells, ↑ Clotting ability, ↑ Immunity DP1/DP2 receptors Increased hematopoietic stem cell proliferation
A-443654 "A4" ↑ Color vision and ↑ Visual resolution Akt/PKB Increased growth and survival of cone photoreceptors
BPIQ-II "B2" ↑ Vision EGFR Promotion of optic nerve growth and regeneration
SB-415286 "S4" Enables limb and organ regeneration GSK3 Activation of Wnt-FGF signaling
LGD2226 "L1" Artificially induces puberty in very young children AR Indirect activation of IGF-I synthesis (puberty)
Demethylasterriquinone B1 "B1" ↑ Muscle mass, ↑ Bone growth INSR, IGF1R Activation of mTOR and protein synthesis
G-1 "G1" ↑ Body size, ↑ Body mass, ↑ Organ mass GPR30 Increased postnatal growth, EGFR transactivation
ZM 336372 "Z3" ↑ Body size and ↑ Blood vessel formation Raf1 Increased postnatal growth, apoptosis suppression


Musculoskeletal

A-769662

The chemical structure of A-769662, an AMPK activator.

  • A-769662: Chemical activator of 5' adenosine monophosphate-activated protein kinase (AMPK)[65]
Chemical Name: 4-hydroxy-3-(2'-hydroxybiphenyl-4-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile
Biological Target: 5' adenosine monophosphate-activated protein kinase (AMPK)[65]
Biological Activity: Induces 44% increase in physical endurance and 23% increase in exercise capacity in untrained subjects[66]
Biological Annotation: AMPK is activated by exercise, and is integral in maintenance of the muscle transcriptome and for oxidative metabolism.[66][67] On a phenotypic scale, AMPK's molecular mechanisms lead to its integral role in exercise endurance.[66] As a master transcriptional regulator, AMPK regulates transcription of metabolism-associated genes in muscle — pharmacological activation of AMPK leads to induction of a novel transcriptional program in muscle that imparts enhanced oxidative metabolism and endurance in muscle.[66] Pharmacological activation of AMPK by A-769662[65] results in a substantial increase in physical endurance and physical capacity even without exercise.[66]


GW1516 Structure

The chemical structure of GW501516, a PPARδ activator.

  • GW501516: Chemical activator of peroxisome proliferator-activated receptor δ (PPARδ)[68]
Chemical Name: 2-(2-methyl-4-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methylthio)phenoxy)acetic acid
Biological Target: Peroxisome proliferator-activated receptor δ (PPARδ)[68]
Biological Activity: Increases exercise endurance by 68% and exercise capacity by 70% in combination with exercise[66]
Biological Annotation: PPARδ is a master transcriptional regulator of skeletal muscle metabolism, and its induction substantially improves exercise endurance.[66] PPARδ appears to increase endurance through three distinct mechanisms: muscular metabolism, mitochondrial biogenesis, and muscle fiber reprogramming.[66] PPARδ expression induces the expression of genes associated with oxidative metabolism and fatty acid uptake, increasing energy uptake and utilization of muscle fibers[66], and it also induces mitochondrial biogenesis, augumenting this effect by increasing capacity for cellular metabolism.[66] Furthermore, PPARδ interestingly reprograms muscle fibers to type I "slow-twitch" fibers, increasing the muscular capacity for endurance.[66] Therefore, pharmacological activation of PPARδ by GW501516[68] leads to substantial changes in muscle that combinatorially lead to significant improvements in physical endurance and capacity.[66]


Resveratrol Structure

The chemical structure of resveratrol, an activator of both sirtuin and 5' adenosine monophosphate-activated protein kinase (AMPK).

  • Resveratrol: Chemical activator of Sirtuin 1 (SIRT1)[69] and 5' adenosine monophosphate-activated protein kinase (AMPK)[70]
Chemical Name: 3,5,4'-trihydroxytrans-stilbene[69]
Biological Target: Sirtuin 1 (SIRT1)[69]
Biological Activity: Doubles physical endurance during exercise[71] and increases average lifespan by 70%[69]
Biological Annotation: Both targets of resveratrol, AMPK and sirtuin, play integral, albeit distinct, roles in general metabolism as well as skeletal muscle physiology.[72] AMPK's roles in skeletal muscle physiology are multifacted — it induces the production of new mitochondria[73] and also enhances fatty acid oxidation (oxidative metabolism)[72][74][75]. In contrast, sirtuin appears to instead enhance mitochondrial activity not by sheer content, but rather transcriptional effects that modify mitochondrial metabolism and also reprogramming of muscle fiber type to slow-twitch and longer-endurance fibers.[70] Taken together, pharmacological activation of both AMPK and sirtuin by resveratrol potently enhances muscle physiology, leading to increased endurance and strength by modulation of both muscular metabolism and mitochondrial function. Furthermore, sirtuin is tightly linked to lifespan — through modulation of bodywide metabolism and adipose tissue consumption[76], resveratrol increases mean lifespan.[69]


SRT1720 Structure

The chemical structure of SRT1720, an activator of Sirtuin 1.

  • SRT1720: Chemical activator of Sirtuin 1 (SIRT1)[77][70]
Biological Target: Sirtuin 1 (SIRT1)[77]
Biological Activity: Increases physical strength and doubles physical endurance during exercise[77]
Biological Annotation: Sirtuin is a critical modulator of bodily metabolism, lifespan, and skeletal muscle physiology.[72] Its roles in lifespan appear to be linked to the fact that sirtuin enhances energy expenditure in metabolic tissues, precipitously decreasing white fat mass[70], that it stabilizes genomic DNA[69], and that it improves cell survival and protects against apoptosis.[78] Sirtuin also is a key regulator of muscle physiology — it enhances endurance by reprogramming Type II "fast-twitch" muscle fibers to Type I "slow-twitch" muscle fibers, and augments mitochondrial activity by enhancing glucose metabolism.[70] Pharmacological activation of SIRT1 by SRT1720 therefore leads to substantial improvements in muscular endurance as well as extension of lifespan.


NP549 Structure

The chemical structure of NP549, an inhibitor of glycogen synthase kinase 3 (GSK3).

  • NP549: Chemical inhibitor of glycogen synthase kinase 3 (GSK3)[79]
Biological Target: Glycogen synthase kinase 3 (GSK3), IC50 ≤ 0.04 nM[79]
Biological Activity: Increases muscle mass
Biological Annotation: During muscle regeneration, Wnt signaling controls the myogenic specification of CD45+/Sca1+ stem cells and is integral for muscle regeneration, with Wnt blockade severely impairing myogenesis during muscular regeneration.[80] Ectopic Wnt signaling strongly promotes the myogenic dedication of these stem cells.[80] Therefore, potent activation of Wnt signaling by GSK3 inhibition by the ruthenium inhibitor NP549[79] leads to dramatic muscular specification of CD45+/Sca1+ stem cells and increased myogenesis and muscle mass.


T0070907 Structure

The chemical structure of T0070907, a peroxisome proliferator-activated receptor γ (PPARγ) inhibitor.

  • T0070907: Chemical inhibitor of peroxisome proliferator-activated receptor γ (PPARγ)[81]
Chemical Name: 2-Chloro-5-nitro-N-4-pyridinylbenzamide
Biological Target: Peroxisome proliferator-activated receptor γ (PPARγ), IC50 = 1 nM[81]
Biological Activity: Converts brown fat into skeletal muscle
Biological Annotation: PRDM16 ("PRD1-BF1-RIZ1 homologous domain containing 16") is a transcriptional regulator that controls a bidirectional fate switch between skeletal muscle and brown adipocytes.[82] PRDM16 reprograms skeletal myocytes to a brown adipogenic lineage; conversely, loss of PRDM16 from brown adipocytes leads to their reprogramming into skeletal myocytes, with adoption of a muscle transcriptiome within days.[82] One of PRDM16's indirect targets is PPARγ; PPARγ facilitates adipogenic reprogramming.[82] Therefore, blockade of the PRDM16-PPARγ pathway by the PPARγ antagonist T0070907[81] leads to direct conversion of brown fat to skeletal muscle, reducing fat mass and increasing muscle mass.


Learning, Memory, and Cognition

FPL 64176 Structure

The chemical structure of FPL 64176, an agonist of voltage-gated L-type Ca+2 channels.

  • FPL 64176: Chemical agonist of voltage-gated L-type Ca+2 channels (LTCCs)[83]
Chemical Name: 2,5-Dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester
Biological Target: L-type Ca+2 channels (Cav1.1, Cav1.2, Cav1.3, and Cav1.4)
Biological Activity: Enhances learning and memory
Biological Annotation: Calcium influx through L-type Ca+2 channels activates calmodulin and a cascade of kinase and transcriptional changes that ultimately lead to synaptic plasticity and long-term potentiation (LTP)[84] as well as putative neural stem cell proliferation.[5] Supporting this, inhibition of L-type Ca+2 channels leads to impairments in spatial memory.[85] Conversely, activation of L-type Ca+2 channels by FPL 64176 potently induces long-term potentiation and enhances learning and memory.


Sulpiride Structure

The chemical structure of (S)-(-)-Sulpiride, a dopamine D2 and D3 antagonist.

  • (S)-(-)-Sulpiride: Non-selective chemical antagonist of the dopamine D2 and D3 receptors[86]
Chemical Name: (S)-(-)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxy-5-sulfamoylbenzamide
Biological Target: Dopamine D1 receptor (Ki = 45 μM), Dopamine D2 receptor (Ki = 15 nM), Dopamine D3 receptor (Ki = 13 nM), Dopamine D4 receptor (Ki = 1 μM), Dopamine D5 receptor (Ki = 77 μM)
Biological Activity: Increased memory storage capacity and enhanced learning and memory
Biological Annotation: Dopamine signaling, including through the D1, D2, and D3 receptors, inhibits the proliferation of neural stem cells.[5] Blockade of dopamine signaling by (S)-(-)-Sulpiride, conversely, enhances the proliferation of neural stem cells and rescues them from apoptosis[5], enhancing neurogenesis. Neurogenesis has been implicated to expand memory storage capacity[87] as well as learning and memory.[88]


Compound 9 Structure

The chemical structure of Compound 9, a putative agonist of NMDA receptors.

  • Compound 9: Tentative chemical agonist of N-methyl-D-aspartate (NMDA) metabotropic glutamate receptors (NMDARs)[89]
Chemical Name: N-Cyclopropyl-5-(thiophen-2-yl)isoxazole-3-carboxamide[89]
Biological Target: N-methyl-D-aspartic acid (NMDA) receptor (tentative)[89]
Biological Activity: Increased memory storage capacity and enhanced learning and memory
Biological Annotation: Excitatory transmission potently induces neurogenesis and neural stem cell differentiation, tentatively linking excitatory activity and a requirement for new neurons for memory storage capacity.[90] This sensing of excitatory transmission is primarily mediated through Ca+2-mediated signaling through L-type Ca+2 channels (LTCCs) and NMDA receptors (NMDARs).[90] Compound 9 is a small-molecule mimetic of local excitatory transmission, potently activating Ca+2 influx through NMDA receptors and leading to rapid genome acetylation and neuronal commitment in neural stem cells, potently inducing neurogenesis in vivo.[89] Neurogenesis has been implicated to expand memory storage capacity[87] as well as learning and memory.[88]


QS11

The chemical structure of QS11, an GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1) inhibitor.

  • QS11: Chemical inhibitor of GTPase-activating protein of ADP-ribosylation factor 1 (ARFGAP1)[91]
Chemical Name: (S)-2-(9-(biphenyl-4-ylmethyl)-2-(2,3-dihydro-1H-inden-5-yloxy)-9H-purin-6-ylamino)-3-phenylpropan-1-ol
Biological Target: GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1)[91]
Biological Activity: Increased memory storage capacity and enhanced learning and memory
Biological Annotation: QS11, an ARFGAP1 inhibitor, is a synergist of Wnt signaling — it does directly activate Wnt signaling, but instead synergizes to enhance Wnt signaling in Wnt-active tissues[91][2], such as the neurogenic hippocampus.[92] Wnt signaling enhances adult hippocampal neurogenesis, and ectopic Wnt signaling enhances neurogenesis.[92][93] Therefore, QS11 controls neural stem cell activity and also learning and memory.[5][87][88]


Neuropathiazol structure

The chemical structure of neuropathiazol, an inducer of hippocampal neurogenesis.

  • Neuropathiazol: Chemical activator of hippocampal neurogenesis[2][94]
Chemical Name: ethyl 4-[methyl-(2-phenyl-1,3-thiazol-4-yl)amino]benzoate
Biological Target: Unknown
Biological Activity: Increases both memory formation and consolidation[95]
Biological Annotation: Neuropathiazol induces the differentiation of adult hippocampal neural progenitor cells (HCN) into neurons at the expense of astrocytes[94], stimulating hippocampal neurogenesis. The adult parahippocampal–hippocampal network is integral in memory, in both formation and consolidation of memories.[95]


TWS119 Structure

The chemical structure of TWS119, a glycogen synthase 3β (GSK3β) inhibitor.

  • TWS119: Chemical inhibitor of glycogen synthase kinase 3β (GSK3β)[96]
Biological Target: Glycogen synthase kinase 3β (GSK3β), IC50 = 30 nM[96]
Biological Activity: Increased memory storage capacity and enhanced learning and memory
Biological Annotation: Wnt signaling plays integral roles in stem cell biology during both development and adult life. Surprisingly, TWS119 directs the neuronal differentiation of pluripotent embryonic carcinoma (EC) and embryonic stem (ES) cells, despite the inhibitory role of Wnt signaling in neural differentiation during gastrulation.[38] Promotion of neurogenesis by TWS119 leads to enhancements in both learning and memory.[87][88]


Cotinine Structure

The chemical structure of (S)-(-)-Cotinine, a nicotinic acetylcholine receptor (nAChR) agonist.

  • (S)-(-)-Cotinine: Chemical agonist of α3β2 and α6β2 nicotinic acetylcholine receptors (nAChRs)[97]
Chemical Name: (S)-1-Methyl-5-(3-pyridinyl)-2-pyrrolidinone
Biological Target: α3β2/α6β2 nicotinic acetylcholine receptors (nAChRs)[97]
Biological Activity: Enhances working and reference memory, increases attention, and increases neuronal survival[52][98][99]
Biological Annotation: The cholinergic system is strongly involved in cognition, and activation of cholinergic signaling has been shown to reverse cognitive deficits.[98] Activation of the cholinergic system has been shown to enhance working and reference memory[98] and attention[99], even in cognitively-impaired subjects, and to improve neuronal survival.[52] (S)-(-)-Cotinine is a nicotine metabolite in humans and is an agonist of specific striatal nicotinic acetylcholine receptors[97], potentiating cognitive-enhancing effects.


O-1783 Structure

The chemical structure of O-1783, a dopamine active transporter (DAT) inhibitor.

  • O-1783: Chemical inhibitor of the dopamine active transporter (DAT) inhibitor[100]
Biological Target: Dopamine active transporter (DAT), IC50 = 17 nM[100]
Biological Activity: Enhances decision making, reaction time, planning, memory, attention, and wakefulness
Biological Annotation: Cognitive enhancers of the 20th century, such as methylphenidate ("Ritalin") and modafinil, were potent inhibitors of the dopamine active transporter (DAT)[101], potentiating strong cognitive-enhancing effects, whose effects appear in part to be mediated by the catecholaminergic system.[102][103][104] Potentiation of dopaminergic transmission leads to highly beneficial effects in executive function, enhancing decision making[102], reaction time[103], memory[103], and wakefulness[104]. These results are recapitulated by a synthetic oxacyclic derivative of methylphenidate, O-1783, which is as equally potent as its precedessor.[100]


Cardiovascular and Circulatory

Hh-Ag1.5

The chemical structure of Hh-Ag1.5, a Smoothened (Smo) receptor agonist.

  • Hh-Ag1.5: Chemical agonist of the Smoothened (Smo) receptor[105]
Chemical Name: 3-chloro-4,7-difluoro-N-(4-methoxy-3-(pyridin-4-yl)benzyl)-N-(4-(methylamino)cyclohexyl)benzo[b]thiophene-2-carboxamide
Biological Target: Smoothened (Smo)[105]
Biological Activity: Potently induces formation of new blood vessels
Biological Annotation: The Hedgehog (Hh) signaling pathway is a morphogen that controls neovascularization in adult tissues.[106] Ectopic Hedgehog stimulation nearly triples capillary density and induces the growth of new large-diameter blood vessels to increase oxygen perfusion of target tissues.[106] This adult neovascularization was recapitulated with Hh-Ag1.5, a potent agonist of Hedgehog signaling.[105]


SNAP Structure

The chemical structure of SNAP, a nitric oxide donor.

  • SNAP: Chemical donor of nitric oxide (NO)[107]
Chemical Name: (S)-Nitroso-N-acetylpenicillamine[107]
Biological Target: Nitric oxide donor, functional mimetic of endogenous nitric oxide synthase (NOS)[107]
Biological Activity: Increases blood flow and induces formation of new blood vessels[107][108]
Biological Annotation: Nitric oxide (NO) is a short-range signaling molecule that plays important roles in the hematopoietic and circulatory systems during both adult life and development.[107][108] In the adult, it induces vasodilation, increasing blood flow, and also induces neovascularization of ischemic tissues.[108] SNAP, a functional agonist of nitric oxide signaling by acting as a stable nitric oxide donor, enhances both blood flow and blood vessel growth through the nitric oxide pathway.


16,16-Dimethyl Prostaglandin E2 Structure

The chemical structure of 16,16-dimethyl Prostaglandin E2, an endogenous DP1 and DP2 receptor agonist.

  • 16,16-dimethyl Prostaglandin E2: Eicosanoid DP1 and DP2 receptor agonist[1]
Biological Target: Eicosanoid DP1 receptor (PTGDR, "Prostaglandin D2 Receptor") and eicosanoid DP2 receptor (GPR44, "G protein-coupled receptor 44")
Biological Activity: Increases oxygen carrying capacity, blood clotting, and immunity
Biological Annotation: The cyclooxygenase (COX)-prostaglandin pathway is a central modulator of hematopoietic stem cell formation and proliferation[49], potently inducing self-renewal of haematopoietic stem cells in the adult.[49] Prostaglandin regulation of haematopoietic stem cells converges on the Wnt/β-catenin pathway.[109] Induction of haematopoietic stem cell proliferation leads to increased formation of haematopoietic lineage cells, increasing oxygen carrying capacity (erythrocytes), clotting (platelets), non-specific immunity (granulocytes, monocytes / macrophages, natural-killer cells), and specific immunity (B lymphocytes and T lymphocytes).


Eyesight and Vision

A-443654 structure

The chemical structure of A-443654, an Akt activator.

  • A-443654: Paradoxical chemical activator of Akt/PKB[110]
Chemical Name: (S)-1-(5-(3-Methyl-1H-indazol-5-yl)pyridin-3-yloxy)-3-(1H-indol-3-yl)propan-2-amine
Biological Target: Akt/PKB (Protein Kinase B)
Biological Activity: Improves color vision and high-resolution vision
Biological Annotation: Retinitis pigmentosa, an incurable disease of blindness, is caused by a progressive loss of cone photoreceptors because of a loss of survival and growth signals through the mammalian target of rapamycin (mTOR) pathway.[111] Conversely, stimulation of Akt, an upstream modulator of mTOR, by a paradoxical chemical activator of Akt, A-443654[110], leads to growth of cone photoreceptors and improvements in color vision and high-acuity vision.


BPIQ Structure

The chemical structure of BPIQ-II, an EGFR inhibitor.

  • BPIQ-II: Chemical inhibitor of the epidermal growth factor receptor (EGFR)[112]
Chemical Name: 8-[(3-Bromophenyl)amino]-1H-imidazo[4,5-g]-quinazoline
Biological Target: Epidermal growth factor receptor (EGFR)
Biological Activity: Enhances growth of the optic nerve during adulthood
Biological Annotation: EGFR mediates the inhibitory effects of myelin (Nogo-66) and chondroitin sulfate proteoglycans (oligodendrocyte myelin glycoprotein) on axonal regeneration.[113] Pharmacological or genetic inhibition of EGFR promotes neurite outgrowth from a number of cell types, and increases axonal regeneration after damage of the optic nerve[113], and blockade of EGFR by BPIQ-II leads to increased optic nerve growth and vision.


Regeneration of Organs and Limbs

SB-415286 structure

The chemical structure of SB-415286, a GSK3 inhibitor.

  • SB-415286: Chemical inhibitor of glycogen synthase kinase (GSK3)[47]
Chemical Name: 3-(3-chloro-4-hydroxyphenylamino)-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione[47]
Biological Target: Glycogen synthase 3 (GSK3), IC50 = 77.5 nM[47]
Biological Activity: Enables regeneration of limbs and organs
Biological Annotation: Lower vertebrates are capable of extensive tissue regeneration even after substantial damage, and this process involves genes in the FGF family (Fgf2, Fgf10, and Fgf20) and the Wnt family (Wnt8 and Wnt10).[114][115][116] Importantly, FGF2 is capable of even regenerating chicken limb buds, which do not naturally regenerate.[115] Wnt signaling is a highly-conserved master regulator of regeneration, controlling limb regeneration (through regulation of FGF signaling)[116] as well as controlling regeneration of the liver and the hematopoietic system.[109] Therefore, ectopic activation of Wnt signaling[25] by pharmacological inhibition of GSK3 by SB-415286[47] leads to regeneration of both limbs and organs in advanced vertebrates such as humans.


Body Size and Organ Size

LGD2226 Structure

The chemical structure of LGD2226, an androgen receptor agonist.

  • LGD2226: Chemical agonist of the androgen receptor[117][118]
Biological Target: Androgen receptor (Ki = 1 nM)[117]
Biological Activity: Artificially initiates puberty, leading to increased muscle mass, bone growth, and sexual progression[117]
Biological Annotation: In males, puberty is initiated by testosterone, which binds to androgen receptors.[118] Abnormally high levels of testosterone young children lead the precocious initiation of puberty, even earlier than the age of five. LGD2226 is a synthetic quinoinone derivative that is an agonist for the androgen receptor[117], mimicking the activities of testosterone and causing skeletal muscle growth, bone growth, sexual maturation[117], and "growth spurts" because of linear bone growth and increases in bone density.


Demethylasterriquinone B structure

The chemical structure of Demethylasterriquinone B, an insulin receptor and insulin-like growth factor receptor agonist.

  • Demethylasterriquinone B1: Chemical agonist of the insulin receptor and the insulin-like growth factor receptor[119]
Biological Target: Insulin receptor (INSR; EC50 = 3-6 μM) and the insulin-like growth factor receptor (IGF1R; 100 μM)
Biological Activity: Increases muscle growth, bone growth, and metabolism
Biological Annotation: Demethylasterriquinone B1 (also known as L-783,281) activates both the insulin receptor and the insulin-like growth factor receptor, which are two structurally-similar and cross-talking pathways that are responsible for the growth of skeletal muscle, the growth of bone, and body growth during the induction of puberty.[119][120][121] Genetic ablation of INSR or IGF1R leads to dwarfism, with retarded muscle and bone growth, as well as mental retardation and other deleterious effects.[121] Concordantly, insulin and insulin-like growth factor (IGF) are known to be anabolic hormones that promote growth and puberty. Therefore, activation of the insulin receptor and the insulin-like growth factor receptor with Demethylasterriquinone B1 mimic puberty and adult growth and increase muscle and bone mass.


G1 Structure

The chemical structure of G-1, a GPR30 agonist.

  • G-1: Selective chemical agonist of G Protein-Coupled Receptor 30 (GPR30)[122]
Biological Target: G Protein-Coupled Receptor 30 (GPR30)[122]
Biological Activity: Increases body size and organ mass
Biological Annotation: GPR30 is an alternative receptor for estrogen, and plays substantial roles in adult growth.[122][123] While estrogen reduces mean body size and height, genetic ablation of GPR30 leads to decreased body size and organ mass, indicating that GPR30 is essential for growth and weight[123]; GPR30's transactivation of the epidermal growth factor receptor (EGFR) pathway may also participate in its growth-enhancing effects.[124] Therefore, selective activation of GPR30 with G-1[122] leads to increased body size, weight, and organ mass.


ZM 336372 structure

The chemical structure of ZM 336372, a Raf1 activator.

  • ZM 336372: Paradoxical chemical activator of Raf1[125]
Chemical Name: N-[5-(3-dimethylaminobenzamido)-2-methyIphenyl]-4-hydroxybenzamide
Biological Target: Raf1 (V-raf-1 murine leukemia viral oncogene homolog 1, c-Raf)
Biological Activity: Increases body size and increased blood vessel formation
Biological Annotation: Raf1 is a Ras GTPase-controlled kinase that is the upstream regulator of the classical mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, a key signaling pathway that controls cell growth and survival.[125][7][126] Raf1-/- mice are growth-impaired and have extensive defects in their vasculature[7][127]; correspondingly, the major function of Raf1 is believed to be inhibition of apoptosis.[7] Therefore, pharmacological activation of Raf1 by ZM 336372[125] leads to both increased body size and increased vascularization.


Augmentation during acute combat


Chemical augumentation during acute combat
Chemical Name Abbreviation Phenotypic Effect Biological Target Mechanism
Batrachotoxin "BX" Maintains brain function and heartbeat even near death Nav channels Reactivation of action potentials
Dobutamine "DB" ↑ Heartbeat, ↑ Breathing, ↑ Blood pressure α/β-adrenoreceptors Non-selective adrenergic signaling
SB-224289 "S2" ↑ Aggression, ↑ Violent behavior 5-HT1B receptor Blockade of modulatory serotonin signaling
(R)-(+)-WIN 55212 "W5" ↓ Pain and alters perception CB1/CB2 receptors Enhanced cannabinoid signaling
JZL184 "J1" ↓ Pain and alters perception MAGL Increased 2-arachidonoylglycerol signaling
Haloperidol "HP" ↑ Animalistic behaviors and ↓ Complex cognitive functions D2-like receptors Neuroleptic activity through dopaminergic blockade
GW 441756 "G4" ↓ Pain TrkA Selective ablation of nociceptive neurons


Combat Physiology

Batrachotoxin structure

The chemical structure of batrachotoxin, a voltage-gated Na+ channel agonist.

  • Batrachotoxin: Chemical agonist of voltage-gated Na+ channels[128]
Chemical Name: (1S)-1-[(5aR,7aR,9R,11aS,11bS,12R,13aR)-1,2,3,4,7a,8,9,1 0,11,11a,12,13-Dodecahydro-9,12-dihydroxy-2-11a-dimethyl -7H-9,11b-epoxy-13a,5a-propenophenanthro[2,1-f][1,4]oxaz epin-14-yl]ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate
Biological Target: Voltage-gated Na+ channels (e.g. Nav1.8)[128]
Biological Activity: Maintains brain function, heart beat, breathing, and muscle contraction even during death-inducing situations
Biological Annotation: Voltage-gated Na+ (Nav) channels are ubiquitously distributed and play pleiotropic roles in the body. They are essential for initiation and conduction of all neuronal action potentials[129] and cardiac action potentials, and therefore Nav channels are a prerequisite for life — without Nav channels, it would be possible to maintain brain function, heart function, lung function, or any form of muscular function. Na+ is the principal excitatory ion of the central nervous system (CNS) and peripheral nervous system (PNS), and also is in part responsible for the pacemaker potential that is the master regulator of heartbeat. During death, ATP-dependent cellular processes begin to break down, leading to the loss of Na+/K+ exchanger activity, loss of separate ionic concentrations across the membrane, and loss of effective electrical conduction. Batrachotoxin artificially "jump-starts" neural activity by ectopic influx of Na+ ions into the cell, regardless of membrane potential, therefore recapitulating action potentials, and ectopically inducing action potentials broadly across the central and peripheral nervous systems as well as the heart. The loss of electrical activity in the brain, spinal cord, and heart found during death begins to be reversed, with ectopic action potentials recapitulating normal physiological activity. While this presents with broad sensory hallucinations and artificial seizure-like motor activities, this allows for effective partial brain function, heart function, and lung function even during cardiac arrest and other life-threatening situations.


Dobutamine structure

The chemical structure of dobutamine, a non-selective α/β-adrenoreceptor agonist.

  • Dobutamine: Non-selective chemical agonist of the α1, β1, and β2 adrenoreceptors[1]
Chemical Name: 4-[2-[[3-(4-Hydroxyphenyl)-1-methylpropyl]aminoethyl-1,2-benzenediol
Biological Activity: Increases heart rate, breathing, and blood pressure
Biological Annotation: The endogenous adrenergic receptor agonist epinephrine induces the "flight-or-fight" response through non-selective activation of α-adrenoreceptors and β-adrenoreceptors.[1] Combinatorially, this dual activation leads to a number of highly rapid and potent physiological changes, including increased heart contraction strength, increased heart rate, bronchodilation, and vasoconstriction of peripheral blood vessels.[1] The sympathomimetic dobutamine mimics these effects, inducing physiological priming that enhances combat capabilities, and also reverses cardiac arrest.


Combat Psychology

SB-224289

The chemical structure of SB-224289, a selective 5-HT1B receptor inhibitor.

  • SB-224289: Chemical inhibitor of the serotonin 5-HT1B receptor[130][131]
Chemical Name: 1'-Methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-y l)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2 ,3-f]indole-3,4'-piperidine[130]
Biological Target: 5-HT1B receptor[130]
Biological Activity: Induces aggression, rage, and hyperactivity
Biological Annotation: The 5-HT1B receptor is necessary for control of aggressive behavior.[51][131][132] Genetic deletion of the 5-HT1B receptor in mice (5-HT1B-/-) leads to increased aggression and violent behavior, while conversely, agonists of the 5-HT1B receptor lead to reduced aggressive behavior.[131][132] Therefore, pharmacological inhibition of the 5-HT1B receptor by SB-224289 leads to increased aggression, rage, and hyperactivity in humans.


WIN 55212 Structure

The chemical structure of (R)-(+)-WIN 55212, a CB1 and CB2 receptor agonist.

Chemical Name: (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone
Biological Activity: Reduces pain and alters perception
Biological Target: Cannabinoid CB1 and CB2 receptor agonist[133][134] (Ki = 62.3 ± 31 nM, CB1 and Ki = 3.30 ± 0.40 nM, CB2)
Biological Annotation: The pain-killing and recreational properties of the drug marijuana (Δ9-tetrahydrocannabinol) have been known since antiquity.[135] Its effects are mediated through the endocannabinoid system, a G-protein-coupled-receptor (GPCR) signaling system that is ubiquitous throughout the body.[135][136] Although the endocannabinoid system is closely linked to pain perception, mechanistic studies have revealed both positive and negative roles of endocannabinoid signaling in nociception; however, indirect agonists are potent analgesics in humans.[136] Therefore, ectopic stimulation of the CB1 and CB2 receptors by (R)-(+)-WIN 55212 leads to reduction in pain and subjective modifications in perception.


JZL184 structure

The chemical structure of JZL184, a MAGL inhibitor.

  • JZL184: Chemical inhibitor of monoacylglycerol lipase (MAGL)[137]
Chemical Name: 4-Nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate[137]
Biological Target: Monoacylglycerol lipase (MAGL), IC100 ≈ 0.25 μM[137]
Biological Activity: Reduces pain and alters perception
Biological Annotation: Anandamide and 2-arachidonoylglycerol are two endogenous agonists of cannabinoid receptors.[137] Although modification of endocannabinoid signaling is possible through synthetic compounds[136], it is also possible to enhance endocannabinoid signaling by modulating levels of endogenous endocannabinoids. 2-arachidonoylglycerol is inactivated by monoacylglycerol lipase (MAGL), thereby terminating its transmission.[137] Pharmacological blockade of monoacylglycerol lipase by JZL184 produces a phenotype indicative of increased endocannabinoid transmission, including analgesia.[137]


Haloperidol Structure

The chemical structure of haloperidol, a dopamine D2-like receptor inhibitor.

  • Haloperidol: Chemical inhibitor of dopamine D2-like receptors
Chemical Name: 4-[4-(4-Chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone
Biological Target: Dopamine D1 receptor (Ki = 80 nM), Dopamine D2 receptor (Ki = 0.1 μM), Dopamine D3 receptor (Ki = 1.2 nM), Dopamine D4 receptor (Ki = 7 nM), Dopamine D5 receptor (Ki = 2.3 nM)[86]
Biological Activity: Induces animalistic behavior and represses higher cognitive functions
Biological Annotation: Dopaminergic signaling is central in cognition and behavior.[1] Pharmacological modulators of dopamine receptors potently modulate behavior, cognition, sleep, seizure activity, and a plethora of other neurological phenomena.[1] Haloperidol, a modestly-selective inhibitor of dopamine D2-like receptors, induces neuroleptic effects in humans, suppressing complex behaviors while preserving animalistic behaviors and primal reflexes.[1] Induction of animalistic behavior in combat substantially enhances combat capabilities.


GW 441756 Structure

The chemical structure of GW 441756, a TrkA inhibitor.

  • GW 441756: Chemical inhibitor of the neurotrophin TrkA receptor[138]
Chemical Name: 1,3-Dihydro-3-[(1-methyl-1H-indol-3-yl)methylene]-2H-pyrrolo[3,2-b]pyridin-2-one
Biological Target: TrkA ("Neurotrophic tyrosine kinase, receptor, type 1"), IC50 = 2 nM[138]
Biological Activity: Confers almost complete protection against pain
Biological Annotation: TrkA is a high-affinity receptor for nerve growth factor (NGF), a key neurotrophin that plays critical roles during development and adult life. Mutations in both TrkA and NGFβ in humans confer congenital insensitivity to pain.[139] During neurological development, NGF/TrkA signaling is responsible for promoting the survival of sensory neurons in the dorsal root ganglion (DRG) responsible for nociception; ablation of NGF/TrkA signaling by GW 441756, a synthetic aza-oxindole inhibitor of TrkA[138], leads to gradual death of nociceptive neurons, thus rendering almost complete protection against pain and a selective and complete absence for the small-diameter and unmyelinated fibers responsible for nociception.


Second-Generation Chemical Augmentations: Modulation of Lifespan and Pain

Main article: Methuselah Program

During the Galactic Era, the second iteration of the Myrmidon Program would heavily rely on the core chemical augmentations of the first generation — the significant upscaling of the number of child subjects, nearly by an order of magnitude, would restrict intensive research and pharmacogenetics to produce further optimizations of the first chemical protocol largely devised by Beah Schore and Kawika Son. However, notably, the UNSC Department of Biological Warfare's collaboration with Acumen Science Laboratories, the Methuselah Program, would mature, generating a list of four chemical compounds that extended lifespan in adult humans.

Two of these compounds, resveratrol and SRT1720, allosteric sirtuin activators, were already serendipitously included in the augmentation protocol, albeit for phenotypic effects beside lifespan extension. However, Methuselah's findings would uncover three more small molecules, mianserin (a serotonin transporter inhibitor)[140], EUK-134 (a superoxide dismutase/catalase mimetic)[141][142], which had both been previously shown to extend lifespan in C. elegans.[140][142], and cycloastragenol (a telomerase activator)[143] —these three molecules were applied combinatorially to extend lifespan, through simulated caloric restriction, abrogation of oxidative stress, and increased telomerase activity, respectively.

Furthermore, a fourth, unrelated compound — fentanyl isothiocyanate (FIT), a highly-potent and irreversible δ-opioid receptor agonist that is a modified, alkylating isothiocyanoto analog of fentanyl[144], was employed to further increase analgesia during combat, rendering the second-generation Myrmidons nearly impervious to pain during combat.

Mianserin structure

The chemical structure of mianserin, a promiscuous inhibitor of serotonin receptors, adrenergic receptors, the H1 histamine receptor, and the norepinephrine receptor.

  • Mianserin: Promiscuous chemical antagonist of various receptors and transporters, notably including the 5-HT2 receptor[140]
    • Biological Targets: Histamine H1 receptor, 5-HT1D receptor, 5-HT2A receptor, 5-HT2B receptor, 5-HT2C receptor, 5-HT3 receptor, 5-HT6, 5-HT7, α1 adrenergic receptor, α2 adrenergic receptor, and norepinephrine transporter
    • Biological Activity: Increases lifespan[140]
    • Biological Annotation: Mianserin, a dibenzazepine tetracycle, is a promiscuous antagonist of serotonin receptors, adrenergic receptors, the H1 histamine receptor, and the norepinephrine receptor, and is employed in human patients as an antidepressant.[140] Pharmacological studies have indicated that serotonin signaling is implicated in C. elegans lifespan — inhibition of serotonin signaling through the 5-HT1 or 5-HT2 receptors (cyproheptadine, methiothepin, mianserin, mirtazepine) increases lifespan, whereas potentiation of serotonin signaling through selective blockade of serotonin transporters (fluoxetine, sertraline, paroxetine) leads to significant decreases in lifespan.[140] In C. elegans, mianserin appears to inhibit homologs of both serotonin and norepinephrine receptors, and its mechanism of action appears to be through the same pathway as dietary restriction, as dietarily-restricted animals did not respond to mianserin.[145] The role of serotonin signaling inhibition in lifespan extension is believed to be based on the role of serotonin as a "food presenting" signal — blocking serotonin is believed to simulate a state of perpetual hunger, therefore generating a neural simacrulum of hunger and leading to lifespan extension.[140][145]


EUK 134 Structure

The chemical structure of EUK 134, a mimetic of superoxide dismutase / catalase.

  • EUK-134: Chemical mimetic of superoxide dismutase / catalase (SOD)[141]
    • Biological Target: 2O2- (superoxide radical)
    • Biological Activity: Increases lifespan[142]
    • 'Biological Annotation: Oxidative stress reduces lifespan by inducing DNA damage, therefore impairing the ability of cells to proliferate.[146] Cells defend against oxidative stress by employing proteins known as superoxide dismutases (SOD), which convert the unstable superoxide radical (2O2-) into peroxide (H2O2), which is subsequently degraded into harmless H2O and O2.[147] Subsequently, chemical facsimile of SOD, through the small molecule EUK-134[141], limits oxidative damage and DNA damage and therefore increases lifespan.[142]


Cycloastragenol structure

The chemical structure of cycloastragenol, a chemical activator of telomerase.

  • Cycloastragenol (TAT-2): Chemical activator of telomerase[143]
    • Biological Target: Telomerase (hTERT)[143]
    • Biological Activity: Increases lifespan[148]
    • Biological Annotation: Telomerase is an unusual reverse transcriptase that is necessary to maintain the integrity of chromosomes during DNA replication[149] Its essential DNA-repairing activity is necessary to repair the genomes of mitotically-active cells, and in fact, telomerase activity induces the proliferation of stem cells[150] and is required to safeguard the genomic integrity of stem cells and to preserve their function[151] Aging is accompanied with DNA damage that limits the function of stem cells, which causes the phenotypic decline typically seen during aging.[151][152] Contrarily, suppression of DNA damage[153] through induction of telomerase[148] increases lifespan. Cycloastragenol, a Chinese natural product otherwise known as TAT-2, is a chemical activator of telomerase in human cells[143], thereby extending lifespan.


Fentanyl isothiocyanate structure

The chemical structure of fentanyl isothiocyanate, an irreversible agonist of the δ opioid receptor.

  • Fentanyl isothiocyanate: Irreversible chemical agonist of the δ opioid receptor[144]
    • Biological Activity: Severely reduces pain during combat[1]
    • Biological Annotation: The δ opioid receptor is a G-protein-coupled receptor (GPCR) that is expressed in the nervous system; its activation leads to the inhibition of GABAergic transmission that represses descending anti-nociceptive circuits[154][155] , thereby relieving inhibition of pain-relieving neural circuitry. Endogenous opioids are believed to the body's resident mechanism to relieve pain and to produce euphoria. Fentanyl isothiocyanate is an isothiocyanato-analog of fentanyl, a synthetic agonist of the δ opioid receptor, and acts by alkylating the receptor, therefore irreversibly activating it[144]. Therefore, application of fentanyl isothiocyanate potently induces analgesia and euphoria, repressing pain imparted in combat.


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